BACKGROUND: Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. PATIENTS AND METHODS: Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. RESULTS: The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 +/- 1110 (range 840-3730) in patients with 7/7 versus 6/6 genotypes, respectively. CONCLUSION: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.
BACKGROUND:Irinotecan (CPT-11) is metabolized by esterase to form a SN-38, which is further conjugated by UGT1A1. Genetic polymorphism has been shown in a promoter region of UGT1A1 and is related to its activity. We investigated whether there might be an inter-individual difference in pharmacokinetics of SN-38 and its glucuronide, depending on the genotypes of UGT1A1. PATIENTS AND METHODS: Nine male patients with lung cancer were treated with irinotecan (50 mg/m2) and carboplatin. Pharmacokinetic parameters were calculated with full sampling plasma data. Genotypes were determined by analyzing the sequence of TATA box of UGT1A1 of genomic DNA from the patients. RESULTS: The genotyping analysis revealed one heterozygote (6/7) and one homozygote (7/7) for (TA)7TAA allele (UGT1A1*28). The remaining seven patients were homozygote for (TA)6TAA allele (6/6, wild type). The metabolic ratios (SN-38/SN-38 glucuronide) in the patient with 7/7 genotype were uncharacteristically higher than those in the patients with other genotypes (6/6 and 6/7). Biliary index was 6980 versus 2180 +/- 1110 (range 840-3730) in patients with 7/7 versus 6/6 genotypes, respectively. CONCLUSION: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.
Authors: Celia N Sanchez-Dominguez; Hugo L Gallardo-Blanco; Mauricio A Salinas-Santander; Rocio Ortiz-Lopez Journal: Exp Ther Med Date: 2018-05-18 Impact factor: 2.447
Authors: Vivaswath S Ayyar; Richard R Almon; Debra C DuBois; Siddharth Sukumaran; Jun Qu; William J Jusko Journal: J Proteomics Date: 2017-03-14 Impact factor: 4.044
Authors: David Church; Rachel Kerr; Enric Domingo; Dan Rosmarin; Claire Palles; Kevin Maskell; Ian Tomlinson; David Kerr Journal: Nat Rev Cancer Date: 2014-05-15 Impact factor: 60.716
Authors: Amy L Pasternak; Kristen M Ward; Jasmine A Luzum; Vicki L Ellingrod; Daniel L Hertz Journal: Physiol Genomics Date: 2017-09-08 Impact factor: 3.107